Comments were received for the following, when they were proposed in the Pharmacopeial
Forum
General Notices:
Section 5.60.30 Elemental Impurities in USP Drug Products and Dietary Supplements
General Chapters:
<124> Erythropoietin Bioassays
<126> Somatropin Bioidentity Tests
<227> 4-Aminophenol in Acetaminophen-Containing Drug Products
<441> Niacin or Niacinamide Assay
<469> Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances
<671> Containers—Performance Testing
<705> Quality Attributes of Tablets Labeled as Having a Functional Score
<736> Mass Spectrometry
<741> Melting Range of Temperature
<781> Optical Rotation
<791> pH
<1111> Bioburden Control of Nonsterile Drug Substances and Products
<1151> Pharmaceutical Dosage Forms
<1181> Scanning Electron Microscopy
<1229.6> Liquid-Phase Sterilization
<1234> Vaccines for Human Use–Polysaccharide and Glycoconjugate Vaccines
<1240> Virus Testing of Human Plasma for Further Manufacture
<1736> Applications of Mass Spectrometry
<2250> Detection of Irradiated Dietary Supplements
Monographs:
L-Alanyl-L-glutamine
Krill Oil Capsules
Azelastine Hydrochloride
Krill Oil Delayed-Release Capsules
Borage Seed Oil
Levobunolol Hydrochloride
Brompheniramine Maleate
Levobunolol Hydrochloride Ophthalmic Solution
Carbamapeine Extended-Release Tablets
Dorzolamide Hydrochloride and Timolol Maleate
Ophthalmic Solution
Mitomycin
Enzacamene
Nicardipine Hydrochloride
Evening Primrose Oil
Oxymetazoline Hydrochloride Ophthalmic Solution
Flax Seed Oil
Paroxetine Extended-Release Tablets
Flunixin Meglumine
Rhodiola Rosea
Gandoderma Lucidum Fruiting Body
Rhodiola Rosea, Powdered
Gandoderma Lucidum Fruiting Body Powder
Rhodiola Rosea Extract, Powdered
Glycyl-L-Glutamine
Rhodiola Rosea Tincture
Glycyl-L -Tyrosine
Risperidone
Hydroxyzine Hydrochloride
Salmeterol Inhalation Powder
Imipramine Pamoate
Sertraline Hydrochloride
Krill Oil
Sodium Phenylbutyrate
Naphazoline Hydrochloride Ophthalmic Solution
Trazodone Hydrochloride Tablets
2
No comments received for the following, when they were proposed in Pharmacopeial Forum
General Chapters
•
•
•
•
<563> Identification of Articles of Botanical Origin
<1081> Gel Strength of Gelatin
<2232> Elemental Contaminants in Dietary Supplements
<1196> Pharmacopeial Harmonization
Compounded Monographs
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Atenolol Compounded Oral Suspension
Atenolol Compounded Oral Suspension, Veterinary
Benazepril Hydrochloride Compounded Oral Suspension, Veterinary
Clopidogrel Compounded Oral Suspension
Doxycycline Compounded Oral Suspension, Veterinary
Enalapril Maleate Compounded Oral Suspension
Lamotrigine Compounded Oral Suspension
Lansoprazole Compounded Oral Suspension
Metronidazole Benzoate Compounded Oral Suspension
Phenoxybenazmine Hydrochloride Compounded Oral Suspension
Piroxicam Compounded Oral Suspension
Prednisolone Compounded Oral Suspension, Veterinary
Prednisolone Sodium Phosphate Compounded Oral Solution
Spironolactone Compounded Oral Suspension
Spironolactone Oral Suspension, Veterinary
Topiramate Compounded Oral Suspension
Monographs
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Acarbose
Acetaminophen Capsules
Acetaminophen Oral Solution
Acetaminophen for Effervescent Oral Solution
Acetaminophen Oral Suspension
Acetaminophen Tablets
Acetaminophen Extended-Release Tablets
Acetaminophen and Tramadol Hydrochloride
Tablets
Aspirin Delayed-Release Tablets
Benazepril Hydrochloride Compounded Oral
Suspension, Veterinary
Butylene Glycol
Carbon Monoxide C11
Chloramphenicol and Prednisolone Ophthalmic
Ointment
Chloramphenicol, Polymyxin B Sulfate, and
Hydrocortisone Acetate Ophthalmic Ointment
Chloroxylenol
Chorionic Gonadotropin
Chorionic Gonadotropin for Injection
Clopidogrel Compounded Oral Suspension
Cupric Sulfate
Cystine
Dexamethasone Oral Solution
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
3
Dextroamphetamine Sulfate Tablets
Dextran 40 in Dextrose Injection
Dextran 70 in Dextrose Injection
Dextrose Injection
Felbamate
Fish Oil Containing Omega-3 Acids Capsules
Fish Oil Containing Omega-3 Acids DelayedRelease Capsules
Flumazenil C11 Injection
Fluphenazine Decanoate Injection
Fluorodopa F18 Injection
Gabapentin
Ginkgo Extract, Powdered
Guar Gum
Glyceryl Behenate
Construct Human Fibroblasts in Polyglactin
Scaffold
Construct Human Fibroblasts in Bilayer
Synthetic Scaffold
Hydralazine Hydrochloride
Invert Sugar
Isofluorophate
Isofluorophate Ophthalmic Ointment
Isopropyl Myristate
Isradipine
Monographs, Continued
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Lithium Citrate
Lithium Oral Solution
Mandelic Acid
Mebendazole
Mephenytoin
Mephenytoin Tablets
Mespiperone C11 Injection
Methionine C11 Injection
Methylparaben Sodium
Mexiletine Hydrochloride
Moricizine Hydrochloride
Neomycin Sulfate and Hydrocortisone Acetate
Ophthalmic Ointment
Neomycin Sulfate and Prednisolone Acetate
Ophthalmic Ointment
Neomycin Sulfate and Prednisolone Sodium
Phosphate Ophthalmic Ointment
Neomycin Sulfate and Triamcinolone Acetonide
Ophthalmic Ointment
Neomycin Sulfate, Sulfacetamide Sodium, and
Prednisolone Acetate Ophthalmic Ointment
Oleovitamin A and D Capsules
Oxaprozin
Pentoxifylline
Physostigmine
Physostigmine Sulfate
Physostigmine Sulfate Ophthalmic Ointment
Pindolol
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
4
Plicamycin
Plicamycin for Injection
Prazosin Hydrochloride
Proguanil Hydrochloride
Propranolol Hydrochloride and
Hydrochlorothiazide Extended-Release
Capsules
Propylparaben Sodium
Raclopride C11 Injection
Ramipril
Reserpine, Hydralazine Hydrochloride and
Hydrochlorthiazide Extended-Release Capsules
Scopolamine Hydrobromide Ophthalmic
Ointment
Sodium Acetate C11 Injection
Sodium Picosulfate
Somatropin
Somatropin for Injection
Sucrose
Tetracaine Ophthalmic Ointment
Valproic Acid Capsules
Vidarabine
Vidarabine Ophthalmic Ointment
Vinpocetine Capsules
Vinpocetine Tablets
Vitamin A
Vitamin A Capsules
Water O15 Injection
General Notices Section:
5.60.30 Elemental Impurities in USP Drug Products
and Dietary Supplements
No. of Commenters:
32
Comment Summary #1: Several commenters suggested, for various reasons,
alternative implementation timing for the application of General Chapters <232>
Elemental Impurities—Limits and <2232> Elemental Contaminants in Dietary
Supplements via the General Notices provision, including, but not limited to:
• Alignment with the implementation of the ICH Q3D Guideline
• A tiered approach for established products
• An open-ended moratorium on implementation
Response: During the period of deferral of this General Notices provision, USP formed
an Advisory Group to consider implementation issues and specific recommendations for
an appropriate implementation time line. Detailed information on the deliberations of the
Advisory Group can be found at http://www.usp.org/usp-nf/key-issues/elementalimpurities. The Council of Experts evaluated the input of the Advisory Group and, based
on those deliberations, determined the new implementation date to be December 1,
2015. This date reflects the Council’s understanding of the requirements for
implementation of the standards by industry and the time required to conform, and
provides an additional eighteen months beyond the date originally proposed.
Comment Summary #2: Several commenters indicated that the reference to “official
substances (drug substances and excipients)” extends the scope of General Chapter
<232> Elemental Impurities—Limits beyond that specified in the General Chapter.
Response: Comment incorporated.
Comment Summary #3: A commenter suggested adding a reference to General
Chapter <2232> Elemental Contaminants in Dietary Supplements.
Response: Comment incorporated. The inclusion of this General Chapter had been
proposed in Pharmacopeial Forum 36(1).
Comment Summary #4: A commenter suggested changing the title of the section to
“Elemental Impurities in USP Drug Products and Dietary Supplements.”
Response: Comment incorporated.
Monograph/Section(s) :
<124> EPO Bioassays/Multiple Sections
Expert Committee(s):
Monographs—Biologics and Biotechnology 2
No. of Commenters:
2
Comment Summary #1: The commenter indicated that the use of an in vivo assay and
the normocythemic mouse reticulocyte assay with an incompletely characterized
erythropoietin stimulating agent (ESA) will not give a good understanding of response in
humans.
Response: Comment not incorporated. The reference standard used in conjunction
with the assay in the General Chapter has been has been calibrated against the World
Health Organization International Standard for EPO using both the normocythemic
mouse bioassay and the exhypoxic polycythemic mouse bioassay. Additionally, the
General Chapter does not apply to all ESAs.
Comment Summary #2: The commenter indicated that the timing of reticulocyte
collection is a critical parameter of the assay and may be dependent on experimental
5
conditions and properties of various ESAs, and that the time for reticulocyte collection
should be specified.
Response: Comment not incorporated. However ,a statement was added to the
introduction to state that the assays and acceptance criteria in this Chapter, and
associated RS are not applicable to forms of EPO that have been engineered to prolong
their half-life, because the General chapter does not apply to all ESAs,.
Comment Summary #3: The commenter requested adding to the Introduction a
definition of what a unit of EPO is, and/or the history of how the unit definition has
evolved. The EPO unit as currently used cannot be applied to all ESAs, because the
unit is based on an in vivo assay of short duration.
Response: Comment not incorporated. However ,a statement was added to the
introduction to state that the assays and acceptance criteria in this Chapter, and
associated RS are not applicable to forms of EPO that have been engineered to prolong
their half-life because the General chapter does not apply to all ESAs,.
Comment Summary #4: The commenter suggested the addition of an example to
illustrate how process-specific units are assigned to the USP Reference Standard
based on the ratio of in vivo to in vivo activity of the test sample, because measurement
of in vivo potency alone may not be reflective of the true activity of an EPO test sample.
in vivo in vivo
Response: Comment incorporated. The text was edited to clarify how the ratio of in
vivo to in vivo activity of the test sample is used to assign a process specific in vivo
assay unit age for the USP Reference Standard.
Comment Summary #5: The commenter requested providing a description of solution
A under assay.
Response: Comment incorporated.
Comment Summary #6: The commenter requested adding a section on Reference
Standards to align with USP’s Style Guide.
Response: Comment incorporated.
General Chapter/Section(s):
<126> Somatropin Bioidentity Tests
Expert Committee(s):
General Chapters—Biological Analysis
No. of Commenters:
1
Comment Summary #1: The commenter requested removal of the in vivo rat based
test as soon as possible and requested a target date for its removal.
Response: Comment not incorporated. The General Chapter contains both the official
in vivo test as well as the new in vivo test to allow manufacturers to verify the new
procedure. USP cannot provide a firm date for the removal of the in vivo test at this
time, but intends to do so as soon as possible.
General Chapter/Sections:
<227> 4-Aminophenol in Acetaminophen—Containing
Drug Products/Multiple Sections
Expert Committee (s):
Monographs—Small Molecules 2
No. of Commenters:
9
Comment Summary #1: The commenters recommended widening the limit of 4aminophenol for solid oral dosage forms and suppositories from NMT 0.01% to NMT
0.15% to reflect current regulatory requirements.
6
Response: Comment incorporated. The acceptance criteria, the Standard solution and
the System suitability section were revised to reflect this change.
Comment Summary #2: The commenter requested including information about other
columns that are suitable for this procedure.
Response: Comment not incorporated. Chromatographic column brand information is
not part of the public standard; it is provided for information only. Additional brands can
be included in the list in the future when supporting data becomes available.
Comment Summary #3: The commenter indicated that the procedure may not be
adequately robust.
Response: Comment not incorporated. The procedure was evaluated by five
laboratories that participated in a collaborative study and was found to be robust.
Comment Summary #4: The commenter requested adding detailed instructions for pH
adjustment in the Buffer section.
Response: Comment not incorporated. The statement about pH adjustment was
deleted. Mixing the proposed concentrations of sodium citrate and citric acid results in
the required pH; no additional pH adjustment is needed.
Comment Summary #5: The commenter requested adding detailed instructions for the
duration of stirring for Solution A.
Response: Comment partially incorporated. The instructions were reworded for clarity.
Comment Summary #6: The commenter recommended revising the Standard stock
solution and Sample stock solution to provide details of the weights and volumes used.
Response: Comment not incorporated. The proposed text is consistent with current
USP format, which allows flexibility in terms of weights and volumes.
Comment Summary #7: The commenter recommended tightening the Relative
standard deviation limit in the Chromatographic Method section.
Response: Comment incorporated. The relative standard deviation was revised to be
5.0% for all dosage forms.
Comment Summary #8: The commenter requested including solution stability profiles
for the Standard solution and Sample solution.
Response: Comment not incorporated. The four-hour storage time for the Standard
stock solution is based on data acquired in multiple laboratories. General Chapter
<227> allows for this timeframe to be extended based on solution stability data acquired
by individual laboratories.
Comment Summary #9: The commenter requested eliminating the need for evaluating
spiked samples to allow multiple lots and products to be evaluated in the same
chromatographic run.
Response: Comment not incorporated. The Expert Committee specifically selected the
single-point standard-addition approach to address the diversity of dosage formulations.
Because of the fragile nature of 4-aminophenol, both in terms of being formed by
hydrolysis of acetaminophen and in terms of degrading and disappearing from solution,
a single-point standard-additions approach is preferred. When the Sample solution and
Standard solution are prepared at about the same time and injected one after the other,
the potential for bias due to matrix affects, kinetics, or other factors is minimized.
Expert Committee-Initiated change #1: Additional changes were made to correct the
text to revise spelling, grammar, and style.
7
Expert Committee-Initiated change #2: The concentration of the System suitability
solution was revised from 0.5 µg/mL to 2.5 µg/mL based on the recommendation of the
Acetaminophen Expert Panel.
General Chapter/Section(s):
<441> Niacin or Niacinamide Assay
Expert Committee(s):
General Chapters—Dietary Supplements
No. of Commenters:
1
Expert Committee-Initiated Change #1: The applicability of each procedure in the
General Chapter was clarified using bullet points.
General Chapter/Section:
<469> Ethylene Glycol, Diethylene Glycol, and
Triethylene Glycol in Ethoxylated Substances/
Impurities
Expert Committee(s):
General ChaptersChemical Analysis
No. of Commenters:
1
Comment Summary #1: The commenter recommended broadening the tailing factor
range to 0.8-2.0 in the System suitability section.
Response: Comment partially incorporated. Based on the data submitted, the Expert
Committee determined that the tailing factor range of 0.8-1.8 is appropriate.
Comment Summary #2: The commenter suggested widening the relative standard
deviation specification in the System suitability section.
Response: Comments not incorporated. The Expert Committee determined that the
submitted data do not support the suggestion, but will consider future revisions upon
receipt of additional supporting data.
General Chapter/Sections:
Expert Committee(s):
No. of Commenters:
<671>Containers—Performance Testing
General Chapters—Packaging, Storage and
Distribution
1
General
Comment Summary #1: The commenter suggested that the testing condition of
40°/75%RH is not appropriate for all situations and that testing conditions should be
determined by the end-user.
Response: Comment not incorporated. Alternate testing methods and procedures can
be used if deemed equivalent or better.
Comment Summary #2: The commenter recommended including Dynamic Vapor
Sorption technology.
Response: Comment not incorporated. Alternate testing methods and procedures can
be used if deemed equivalent or better.
Comment Summary #3: The commenter recommended the inclusion of a water-filled
blister permeation (by weight loss) method.
Response: Comment not incorporated. Alternate testing methods and procedures can
be used if deemed equivalent or better.
8
Comment Summary #4: The commenter recommended that other procedures for
handling aberrant data and should allow end-user the flexibility to choose be
recognized.
Response: Comment incorporated. The Expert Committee agreed that all data should
be reviewed for anomalies and these methods should follow any established standard
procedures for analysis.
Comment Summary #5: The commenter recommended revising the classification (tight
and well-closed) of the currently official methods.
Response: Comment not incorporated. However, the Expert Committee agreed that
classification system needs to be revised and an Expert Panel has been formed to
address the deficiencies in the current classification system.
Comment Summary #6: The commenter recommended removal of any requirement for
pharmaceutical manufacturers to classify their container closure systems, e.g., bottle
systems as tight container or blisters as Class A.
Response: Comment not incorporated. However, the Expert Committee agreed that
the classification system needs to be revised and an Expert Panel has been formed to
address the deficiencies in the current classification system.
Definitions
Comment Summary #7: The commenter suggested adding definitions for low/high
barrier bottle systems.
Response: Comment not incorporated. The definitions for unit-dose containers is
meant to define the duration and MVTR expected for a package system, which can be
applied to low or high barrier multi-unit containers.
Comment Summary #8: The commenter requested the deletion of the definition for
“Test Unit,” because the term “Sample” is more universally understood and accepted.
Response: Comment not incorporated. The Expert Committee decided current
terminology was appropriate.
Comment Summary #9: The commenter recommended deleting the reference to
ASTM E-96, because the reference document does not discuss the advantages of
weighing more units, as stated in the General Chapter.
Response: Comment incorporated.
Barrier Protection Determination for Packaging Systems for Solid Oral Dosage
Forms
Comment Summary #10: The commenter suggested that instead of the reference to
ASTM D7709, a more general reference would be more appropriate to avoid future
divergence between USP and ASTM.
Response: Comment incorporated. The sentence was revised to clarify that the
method is based on the ASTM D7709.
Barrier Protection Determination for Packaging Systems for Solid Oral Dosage
Forms—Desiccants
Comment Summary #11: The commenter recommended drying desiccant for two
hours instead of seven hours.
9
Response: Comment not incorporated Based on data presented at the USP Moisture
Permeation Workshop in 2013, water activity of the desiccant is also dependent on the
sample size being dried. If there is a large quantity, more than four hours is required.
Barrier Protection Determination for Packaging Systems for Solid Oral Dosage
Forms—Procedure
Comment Summary #12: The commenter suggested a test sample set of six instead of
15.
Response: Comment not incorporated. The sample number proposed in General
Chapter was based on statistical analysis.
Comment Summary #13: The commenter recommended allowing the end-user the
option of removing the outer closure of an induction sealed bottle, because leaving the
closure in place can increase variability
Response: Comment incorporated A clarifying statement was added on how to
increase precision by removing the closure.
Comment Summary #14: The commenter suggested controlling the temperature and
humidity during the equilibration step at ± 5° and ± 5% RH.
Response: Comment not incorporated. The suggested temperature and humidity
tolerance is too stringent and could be difficult to implement for some stakeholders.
Comment Summary #15: The commenter suggested that minimum fill of the container
can be determined on the sample and thus the reference to ASTM is not necessary and
can be deleted.
Response: Comment incorporated.
Comment Summary #16: The commenter suggested that the pre-storage weighing
instruction is not necessary and should be omitted.
Response: Comment not incorporated. The instructions are intended to limit the
amount of time that samples are outside the test conditions.
Comment Summary #17: The commenter recommended providing information on the
control of temperature and RH for the equilibration step, which can increase variability.
Response: Comment incorporated.
Comment Summary #18: The commenter requested replacing the term “specimen”
with the term “sample,” because it is more universally understood and accepted.
Response: Comment not incorporated. The Expert Committee decided that the current
terminology was suitable.
Barrier Protection Determination for Packaging Systems for Solid Oral Dosage
Forms—Calculations
Comment Summary #19: The commenter suggested an alternate moisture vapor
transmission rate calculation.
Response: Comment not incorporated. The General Chapter does not restrict the use
of alternate calculations and analysis of the data.
Comment Summary #20: The commenter recommended deleting the requirement for
sample weighing at time zero.
Response: Comment not incorporated. The day zero time point is used for the low
barrier calculations. The intent is to clarify that it is not used for the regression
calculation.
10
Comment Summary #21: The commenter suggested that Method 3 be optional with a
provision for testing low barrier blisters according to Method 2 at 25°/60%RH or other
temperatures.
Response: Comment not incorporated. It is recognized that there is some sacrifice in
accuracy for low barrier blisters using the two day method at 40°/75%. The primary
purpose of the method is to allow comparison across container closure systems
Comment Summary #23: The commenter recommended not having a fixed number of
samples and indicated that six should be a minimum.
Response: Comment not incorporated. The accuracy of the method was developed
and is supported by a sample size of 10. If an alternate sample size is used this will
need to be described and justified in the reporting of the results.
General Chapter/Section(s):
<705> Quality Attributes of Tablets Labeled as
Having a Functional Score/Multiple Sections
Expert Committee:
General Chapters—Dosage Forms
No. of Commenters:
5
Comment Summary #1: The commenter requested clarifying that the General Chapter
covers tablets with approved labeling indicating that the tablets can be split into multiple
portions that have corresponding fractional doses.
Response: Comment incorporated.
Comment Summary #2: The commenter requested that the sentence, “Disintegration
testing is required only when approved as a surrogate for dissolution and specified in
the monograph” be removed from the Purpose section as it is repeated under the
Disintegration section.
Response: Comment incorporated.
Comment Summary #3: The commenter requested removal of the sentence, “The
dose of the split tablet portions should be stated on the product labeling” from the
Purpose section.
Response: Comment incorporated.
Comment Summary #4: The commenter requested removing the instructions for the
testing to be performed promptly after splitting the tablets.
Response: Comment incorporated.
Comment Summary #5: The commenter requested that the procedure allow other
justified tablet splitting methods instead of splitting by hand.
Response: Comment not incorporated. The Expert Committee determined that hand
splitting is representative of rudimentary practice by patients and is preferable than
allowing the multitude of available splitting devices for this procedure.
Comment Summary #6: The commenter indicated that the test for Splitting Tablets
with Functional Scoring should be brought into alignment with the FDA Guidance for
Industry—Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation. There are
specific differences between the General Chapter and FDA’s Guidance in sample size,
additional confirmation of the ability of split portions to meet USP <1216> Tablet
Friability, and the metric of comparing the weight of the split portion to the expected
fractional weight based on the weight of the intact tablet.
Response: Comment not incorporated. The Expert Committee determined that this test
applies to tablets reviewed for scoring functionality based on the expectations for
content uniformity, friability, and loss of mass detailed in the FDA Guidance document.
11
The Expert Committee finds that the Splitting Tablets with Functional Scoring test
incorporates elements of uniformity and loss of mass and provides a simplified
demonstration that tablets having approved labeling can be split with the resulting split
portions approaching the expected weight.
Comment Summary #7: The commenter requested that only one of the split portions
resulting from an intact tablet should be used for the dissolution test sample.
Response: Comment not incorporated. The Expert Committee found that the selection
of a single split portion from an intact tablet can also be a source of bias for subsequent
test results.
General Chapter/Section(s):
Expert Committee(s):
No. of Commenters:
<736> Mass Spectrometry/Multiple Sections
General Chapters—Chemical Analysis
8
Introduction
Comment Summary #1: The commenter indicated that the term “molecular weight”
should be avoided when referring to the determination by mass spectrometry and
“molecular mass” should be used instead.
Response: Comment incorporated. Weight changed to “molecular mass or m/z”
throughout General Chapter.
Comment Summary #2: The commenter suggested use of the word “technique”
instead of “method.”
Response: Comment incorporated. “Method” was changed to “technique” or
“procedure” as appropriate throughout the General Chapter.
Qualitative Analysis
Comment Summary #3: The commenter indicated that high resolution mass
spectrometers (HRMS) do not preclude accurate mass. The commenter suggested
adding the sentence, “Tighter tolerances on mass accuracy are also afforded using
HRMS”
Response: Comment incorporated. The following sentence was added, “Also, tighter
tolerances on mass accuracy are also afforded using high-resolution mass spectrometry
(HRMS).”
Qualitative Analysis, Experimental Parameters
Comment Summary #4: The commenter recommended providing a description of a
“large biomolecule” that includes minimum molecular size (for example; mass in
Daltons), because it is not clear if the term “large biomolecules” refers only to large
macromolecules such as proteins and nucleic acids.
Response: Comment incorporated. The prefix “bio” was deleted and a mass lower limit
of 2000 m/z was added to the description.
Comment Summary #5: The commenter suggesting revising the Mass Resolution
section to read “A demonstration… of the instrument’s established performance
qualification (PQ) procedure if run daily or prior to the time of use,” because not all PQ
tests are method specific, and System Suitability needs to be performed prior to testing
12
of samples. If this test is listed under System Suitability and is performed as part of PQ
there would be a discrepancy.
Response: Comment incorporated. The Expert Committee revised the last sentence of
the section to state, “A demonstration of the appropriate resolution is included in the
system suitability tests for a procedure. The performance test in the instrument’s
established PQ executed daily or prior to the time of use may suffice.”
Qualitative Analysis, Interpretation Directions
Comment Summary #6: The commenter suggested changing the phrase, “The
definitive and most certain identification…” to “identification…”
Response: Comment incorporated.
Comment Summary #7: The commenter indicated that both MS/MS and accurate
mass capabilities are accessible and that a minimum of three ions may be overly
restrictive. The commenter suggested the addition of the text, “the spectrum of the
standard should closely resemble that of the sample and a minimum of three structurally
relevant ions, one of which is an ion representing the molecular mass of the analyte,
should be used for the comparison. In the case where only the ion representing the
intact molecule is produced, the accurate mass or MS/MS spectrum of the molecular ion
may be used to strengthen the identification.”
Response: Comment incorporated.
Quantitative Analysis
Comment Summary #8: The commenter indicated that MS is not specified only for
“organic” analytes.
Response: Comment incorporated. The Expert Committee removed the word “organic.”
Quantitative Analysis, System Suitability
Comment Summary #9: The commenter suggested adding information to indicate that
the parameters precision, linearity, accuracy, and quantitation limit can be shown once
for system suitability in the scope of the validation. Otherwise the General Chapter
might be interpreted as a requirement for each release testing. Regarding the practical
performance of analytical release testing, it is not possible to include these parameters
in each system suitability testing.
Response: Comment partially incorporated. The Expert Committee added the caveat
“as appropriate.”
Comment Summary #10: The commenter indicated that ±0.50 m/z mass accuracy
may not be adequate, because ±0.50 is not sufficient for quantitation and recommend a
value of ±0.20.
Response: Comment not incorporated. The Expert Committee determined that while
tighter criteria can be achieved on many instruments, it is not necessary for quantitative
analysis when a modest deviation from ideal mass accuracy can be taken into account
by using a known reference standard–the exact target analyte–to set up the method.
Comment Summary #11: The commenter suggested including one or two examples in
the accuracy section for when quality control (or check) samples may also be
appropriate for inclusion in the procedure.
13
Response: Comment not incorporated. The Expert Committee determined that it was
not essential to add an example. The wording is only meant to highlight the option that
it may be appropriate to include quality control samples.
Comment Summary #12: The commenter indicated that the Quantitative Limit section
should focus on limits of validated range (demonstrated by accuracy and precision)
rather than discussion on limit tests and signal-to-noise ratio requirements.
Response: Comment not incorporated. The Expert Committee determined that
accuracy and precision criteria were adequately described in the System suitability
section.
Qualification of Mass Spectrometry Instruments, Operational Qualification
Comment Summary #13: The commenter suggested revising the following phrase to
state, “MS instruments should be qualified against target specification for the intended
application or manufacturer specifications if suitable,” instead of “not simply the
specifications supplied by the manufacturer.”
Response: Comment not incorporated. The Expert Committee determined that while
manufacturer specifications may work in some cases, the intended purpose is always
the driver.
Qualification of Mass Spectrometry Instruments, Performance Qualification
Comment Summary #14: The commenter indicated that the sentence, “Methodspecific PQ tests, also known as system suitability tests, may be used in lieu of PQ
requirements for validated procedures” implies that PQ is used to prove the instrument
functions properly after certain intervals, and that system suitability is used to prove that
a specific instrument, at a specific time point, is capable of correctly analyzing a specific
product. Therefore, it appears that the statement would only be true when both sets of
tests were the same, which appears to conflict the purpose of each test, PQ for the
instrument, and, SS for the product). Validation of the procedure typically is different
from PQ’s proving that an instrument is working properly at different intervals in time
(e.g., every 6 months). If a PQ and SS test were exactly the same, then the results
could be used to show that the instrument is running properly and is capable on that day
to run a specific product. Assuming the PQ and SS were the same, SS results might be
utilized as a part of a validation; however, one would hope a method was validated well
in advance of running actual samples with released results.
Response: Comment not incorporated. The system suitability test is not positioned as
a test to be performed on the same frequency as a separate PQ test (e.g. 6 months).
The system suitability test would be performed prior to use, each time the validated
method were executed.
Comment Summary #15: The commenter recommend revising the text as follows for
clarity, “Periodic PQ calibration or verification should include a subset of the
OQ...Depending on typical use, the specifications for PQ specification criteria may be
higher or lower than the manufacturer's installation specifications more or less stringent
depending on end user needs
Response: Comment not incorporated. “PQ” is the standard language utilized in USP
General Chapters. The Expert Committee determined that these changes were not
necessary.
14
Comment Summary #16: The commenter recommended revising the section to clarify
the intent of “Periodic PQ” as compared to “system suitability.” As currently presented,
the “Periodic PQ” definition and intent are lost and intertwined with the term “system
suitability” intent. Periodic PQ is intended for general system qualification activities, and
“system suitability” is used to show that the system is acceptable for a particular defined
test/analysis.”
Response: Comment not incorporated. The system suitability test is not positioned as
a test to be performed on the same frequency as a separate PQ test (e.g. 6 months).
The system suitability would be performed prior to use, each time the validated method
were executed.
Comment Summary #17: The commenter indicated that PQ in the sentence, “For
qualitative applications, the PQ experiment includes a check of the mass accuracy of
the instrumentation,” would be identical to a daily mass accuracy check of the
instrument or what is sometimes called a “check tune.” The commenter suggested
discussing this as part of the PQ assessment, because if this “check tune” does not
meet prescribed mass accuracy the instrument parameters are typically “re-tuned” to
meet the mass accuracy needed.
Response: Comment not incorporated. Each instrument manufacturer may call the PQ
experiment something different. The Expert Committee determined that the sentence
as written is appropriate.
VALIDATION AND VERIFICATION OF MASS SPECTROMETRY ANALYTICAL
PROCEDURES
Expert Committee-Initiated Change #2: The sentence, “The required validation
performance characteristics of an MS analytical procedure are listed in Table 1,” was
replaced with the following sentences, “The required validation performance
characteristics of an MS analytical procedure, assuming the typical Category 1 USP
specifications of 98.0-102.0% for drug substance and 95.0-105.0% for drug product, are
listed in Table 1. The actual validation performance characteristics would be dependent
upon the specifications in place and should provide sufficient evidence that the
measurement capability is sufficient for those specifications.” The Expert Committee
determined that the criteria presented in Table 1, particularly those for accuracy and
precision, are designed to provide assurance of minimum procedure capability for the
various monograph acceptance criteria. The criteria presented in Table 1 are consistent
with the criteria used for the validation of chromatographic procedures. Procedures
applying mass spectrometry may not be capable of meeting these criteria (Table 1).
Public comments on previously published spectroscopy general chapters have raised
similar issues. Although certain spectroscopic method limitations (by comparison with
the proposed acceptance criteria) undoubtedly exist, the absolute need for appropriate
procedure capability has been given precedence in the establishment of the criteria.
From a practical viewpoint, these limitations may preclude the use of a given
spectroscopic method for a specific application. In rare instances, only one
spectroscopic method can be used for a given quality attribute, and the criteria (Table 1)
cannot be met; however, these instances are indeed the exception rather than the rule
and will be managed accordingly.
15
Comment Summary #18: The commenter indicated that it is unclear how the proposed
General Chapter should be applied to MS used as detection system for GC and HPLC.
In those cases they indicated that the ICH documents on "Validation of Analytical
Procedures" and General Chapter<1225> should be applied and should prevail.
Response: Comment not incorporated. The Expert Committee determined that the use
of MS as a detection system is included in the scope of this General Chapter.
Comment Summary #19: The commenter indicated that for “quantitative determination
of impurities (Category II)”, mass spectrometry tests may be an additional test for
genotoxic impurities at the trace (ppb to ppm) level based on new guidance by
EMEA/CHMP/QWP/251344/2006.
Response: Comment not incorporated. The Expert Committee will consider future
revisions to the monograph upon receipt of supporting data.
Table 1. Analytical Measurement Requirements
Comment Summary #21: The commenter recommended revising Table 1 to reflect
limit tests, because mass spectrometry methods are often used to achieve specificity
and or sensitivity when more conventional techniques cannot and these are often limit
tests. The table currently reflects routine quantitative analyses, which are not typical.
Response: Comments not incorporated. The Expert Committee determined that the
limits proposed are appropriate. See Expert Committee-Initiated Change #2.
Comment Summary #22: The commenter asked for clarification of the term rNLT
Response: Comment incorporated. The phrase “correlation coefficient (R) must not be
less than (NLT)…” was added.
Comment Summary #23: The commenter recommended changing the range
requirement for Category I to +/- 20% to be consistent with 100% centered, because
often 85% to 115% is acceptable.
Response: Comment not incorporated. The Expert Committee determined that the
limits are appropriate. See Expert Committee-Initiated Change #2.
Comment Summary #24: The commenter requested to change the range requirement
for Category II tests to 50-150%, because impurity levels often vary with a larger range.
Response: Comment not incorporated. The Expert Committee determined that the
limits are appropriate. See Expert Committee-Initiated Change #2.
Comment Summary #25: The commenter suggested that the Range criteria under
Category II be clarified, because it is not clear what this range refers, only that it relates
to impurities.
Response: Comment not incorporated. The range is relative to Category II tests as
stated in General Chapter <1225>. See Expert Committee-Initiated Change #2.
Comment Summary #26: The commenter indicated that the accuracy criteria for
Category I tests are too tight for MS quantitation, because accuracy will depend on MS
response and may still have poor response, even if it is the main component, and
suggested a +/- 10% for drug substance and drug product.
Response: Comment not incorporated. The Expert Committee determined that the
limits are appropriate and noted that if these criteria cannot be met, then MS is not the
appropriate technique to employ.
16
Comment Summary #27: The commenter suggested that the repeatability criteria for
Category I tests are too tight for MS response and suggested a NMT 10% for drug
substance and drug product.
Response: Comment not incorporated. The Expert Committee determined that the
limits are appropriate. See Expert Committee-Initiated Change #2.
Comment Summary #28: The commenter indicated that the intermediate precision
criteria for Category I tests are too tight for MS response and suggested a NMT 15% for
drug substance and drug product.
Response: Comment not incorporated. The Expert Committee determined that the
limits are appropriate. See Expert Committee-Initiated Change #2.
Comment Summary #29: The commenter indicated that the intermediate precision
criteria for Category II tests are too tight.
Response: Comment not incorporated. The Expert Committee determined that the
limits are appropriate. See Expert Committee-Initiated Change #2.
Comment Summary #30: The commenter suggested including criteria on limit and
Category IV tests.
Response: Comment partially incorporated. See Expert Committee-Initiated Change
#2
Comment Summary #31: The commenter suggested that the column headers could be
clearer.
Response: Comment not incorporated. The definitions are made clear for the intended
purpose in General Chapter <1225>.
Comment Summary #32: The commenter recommend adding a separate table,
similar to Table 1, specifically for biologics, or eliminating Table 1 altogether and instead
make specific reference to other USP General Chapters for small molecules and
biologics requirements, because Table 1 makes no reference to possible differences
between small molecules and biologics and does not reflect the wider acceptance
criteria of biologics.
Response: Comment not incorporated. The Expert Committee determined that large
molecules will have to be addressed on a case-by-case basis, making it difficult to
provide a meaningful table. The submitter can make their justifications in their
monograph submissions on a case by case basis. The Expert Committee will take the
comment under consideration for future updates to the General Chapter.
Comment Summary #33: The commenter suggested changing the linearity
requirement for Category II test to correlation coefficient NLT 0.98.
Response: Comment not incorporated. The Expert Committee determined that the
criterion is appropriate. See Expert Committee-Initiated Change #2
Comment Summary #34: The commenter indicated that Table 1 should include
stability requirements as a category, because there is a section at the end of this
General Chapter that mentions solution stability.
Response: Comment not incorporated. The Expert Committee determined that the
stated criteria are appropriate. See Expert Committee Change #2.
Comment Summary #35: The commenter indicated that the acceptance criteria listed
in Table 1 are very strict for mass spectrometry, because they are stricter than HPLCUV methods and will be difficult to meet them all for all Category I.
17
Response: Comment not incorporated. The Expert Committee determined that the
criteria are driven by the general validation criteria and not by the technique. See Expert
Committee-Initiated Change #2.
Section: Analytical Procedure Validation
Comment Summary #36: The commenter indicated that the statement “These
(Robustness tests) can include measuring the stability of the analyte under specified
storage or ionization conditions” should also include appropriate chromatographic
conditions, such as flow rate, mobile phase composition, etc.
Response: Comment incorporated.
General
Comment Summary #37: The commenter requested combining this General Chapter
with General Chapter <1736> Applications of Mass Spectrometry as the information in
both General Chapters is applicable to the Mass Spectrometry.
Response: Comment not incorporated. The Expert Committee followed the strategy
developed and published in a Stimuli Article “An Alignment of Concepts and Content
across the Spectroscopy General Chapters in the United States Pharmacopeia–
National Formulary (USP–NF)”; Pharmacopeia Forum 40(1) [Jan.–Feb. 2013].
Comment Summary #38: The commenter indicated that the General Chapter titles for
<1736> and <736> appear to be mismatched, because more general MS information is
provided in the applications General Chapter <1736> than in General Chapter <736>,
and the qualitative and quantitative analysis and expected system suitability and criteria
in <736> should be included in <1736>
Response: Comment not incorporated. The Expert Committee determined that the
content and concepts are aligned with the strategy discussed in the Stimuli Article “An
Alignment of Concepts and Content across the Spectroscopy General Chapters in the
United States Pharmacopeia–National Formulary (USP–NF)”; Pharmacopeia Forum
40(1) [Jan.–Feb. 2013].
General Chapter/Section(s):
Expert Committee(s):
No. of Commenters:
<741> Melting Range or Temperature/Procedures
General Chapters—Physical Analysis
2
Comment Summary #1: The commenters proposed removing the sample height
requirement for tests performed with Apparatus II and replacing it with a statement
indicating that the vendor recommendations for sample height should be followed,
based on differences in the design of the heating block and optical (or other) detection
system, and in order to avoid impact in the accuracy of the measurement.
Response: Comment incorporated. A nominal height of 3 mm is now prescribed, and a
new statement is incorporated stating that, “Due to the instrument design, alternative
sample sizes may be instructed by the instrument manufacturer.”
18
General Chapter/Section(s):
Expert Committee(s):
No. of Commenters:
<781> Optical Rotation/Multiple Sections
General Chapters—Physical Analysis
1
Introduction
Expert Committee-Initiated Change #1: The definitions of dextrorotatory and
levorotatory (optical isomers) were updated for clarity.
General
Comment Summary #1: The commenter requested the usage of the suffix “⁰C” for all
references to temperature, because the use of “⁰” is also used to reference optical
rotation and may cause confusion.
Response: Comment incorporated.
Comment Summary #2: The commenter recommended adding a footnote clarifying
that all references of wavelengths are in vacuum. The sodium D line is 589.44 in
vacuum and 589.3 in air.
Response: Comment incorporated.
Introduction
Comment Summary #3: The commenter suggested replacing the reference to the
wavelength of 578 nm, because there are no monographs that have this optical rotation
and it is very close to 589 nm, the standard wavelength used by most monographs. In
lieu of 578 nm, the commenter recommended mentioning 325 nm, because some
monographs make reference to this wavelength.
Response: Comment incorporated.
Comment Summary #4: The commenter requested keeping the contact data of the
unique supplier of NIST traceable quartz calibration standards.
Response: Comment incorporated. A revised footnote was reintroduced.
Procedures
Comment Summary #5: The commenter recommended the removal of the
requirement of a 1.0-dm tube, because there are monographs that use other lengths.
Response: Comment not incorporated. The General Chapters states “unless otherwise
directed” to accommodate exceptions. The majority of monographs use a 1.0-dm tube.
Comment Summary #6: The commenter recommended removing the temperature
requirement of 25⁰C, because there are monographs stating different temperatures for
measurement.
Response: Comment not incorporated. The General Chapter states “unless otherwise
directed” to accommodate exceptions. The standard temperature for both optical
rotation and specific rotation measurements is 25⁰C.
19
General Chapter/Section(s):
Expert Committee(s):
No. of Commenters:
<791> pH/Multiple Sections
General Chapters—Chemical Analysis
7
General
Comment Summary #1: The commenter recommended using the international
terminology outlined in ISO Guide 99 International Vocabulary of Metrology.
Response: Comment not incorporated. This recommendation requires a thoughtful
evaluation and, if it is accepted would require change in all of the USP standards for
consistency. The Expert Committee will consider it in future revisions to the general
chapters.
Instrument Requirements
Comment Summary #2: The commenter requested clarifying the requirement for the
accuracy of the temperature measurement system from “at least 1⁰C” to “±1⁰C.”
Response: Comment incorporated.
Comment Summary #3: The commenter requested clarifying the requirement of the
resolution of the temperature measurement system from “at least 0.1⁰C” to “not more
than 0.1⁰C.”
Response: Comment not incorporated. The Expert Committee finds the current
wording of this statement to be sufficient.
Comment Summary #4: The commenter suggested harmonizing the temperature for
measurements with the Eur.Ph. to be 20-25⁰C instead of the current 25±2⁰C.
Response: Comment not incorporated. This is not a fully harmonized document. The
calibration requirements are harmonized within Table 2. However, the current text is
more flexible than Eur.Ph. regarding temperature by stating that“… temperatures
outside this range are acceptable…” For example, a testing criteria defined by the user
to be 25±2⁰C satisfies both USP and Eur.Ph. specifications.
Comment Summary #5: The commenter suggested revising the note on challenges in
applying non-aqueous systems to pH measurements based on systems standardized to
aqueous buffers from “… nonaqueous solutions or (any) suspensions…” to “…
nonaqueous systems…” to generalize the application.
Response: Comment incorporated.
Measurement System
Expert Committee-Initiated Change #1: The title of the section was changed to:
“Buffer Solutions for Standardization of the pH Measurement System,” to describe the
content of the section more accurately.
20
Comment Summary #6: The commenter requested that a wider labeled accuracy, than
±0.02 pH units, be considered for buffer solutions greater than pH 12, because there
are no such buffer solutions commercially available.
Response: Comment not incorporated. There are several commercially available
buffer solutions greater than pH 12 in compliance with the specification of ±0.02 pH
units.
Comment Summary #7: The commenter suggested stating that for buffer solutions
lower than pH 11, only prepared buffers and not commercially available buffers can be
used.
Response: Comment not incorporated. The Expert Committee did not find it necessary
to dictate whether the pH buffer solutions shall be self-prepared or commercially
supplied.
Comment Summary #8: The commenter suggested the addition of a pH 7.01 buffer
solution in Table 2, because it is one of the most common pH buffer solutions used for
standardization.
Response: Comment not incorporated. There is potential difficulty in the traceability of
the precise weight of sodium hydroxide into a phosphate salt during the preparation of
the pH 7 buffer, due to the hygroscopic nature of the sodium hydroxide. pH 7.01 buffer
solution has not been listed in USP or Eur.Ph. pH buffer solutions. NIST offers many pH
buffer Certified Reference Materials, but they do not offer one at 7.0 pH.
Calibration
Comment Summary #9: The commenter recommended clarifying whether the
temperature at which the calibration is performed should be concordant with the
temperature of subsequent sample measurements.
Response: Comment not incorporated. The sample should be prepared according to
the specific monograph instructions, if any. There is no requirement in <791> to assure
that the temperatures of the calibration buffer solutions and the sample(s) need to be
the same (or close). The user shall determine the sample temperature.
Comment Summary #10: The commenter requested adding the provision “preferably”
in the selection of buffer solutions for standardization in order to provide more flexibility,
and consistency with the footnote for the use of other buffers. This change is also
consistent with the language in the Eur.Ph.
Response: Comment incorporated.
Comment Summary #11: The commenter requested clarifying that pH values should
be linearly interpolated as a function of temperature, according to Table 2, where the
calibration temperature falls at values intermediate of the 5⁰C data intervals provided.
Response: Comment incorporated. A new sentence was added in the Calibration
section, item 4 for temperatures not included in Table 2.
21
Comment Summary #12: The commenter requested clarifying that automatic
temperature compensation is a feature that only applies to calibration.
Response: Comment partially incorporated. The temperature compensation (for Nernst
equation) can be performed manually or automated during the calibration and operation.
A new sentence was added in the introduction of the Operation section.
Comment Summary #13: The commenter recommended clarifying the text to perform
offset verification after the first calibration point to allow application to more pH meters
within the scope.
Response: Comment not incorporated. The offset and slope can only be measured
after the 2-point calibration process is completed.
Comment Summary #14: The commenter requested reviewing the acceptable
requirement of the range for slope of the two point calibration of 95-105% to 90-100%.
Response: Comment partially incorporated. The acceptable slope range was changed
to 90-105%.
Comment Summary #15: The commenter suggested changing the slope and offset to
be defined by the user of the pH meter, because the acceptable range depends on the
use of the pH meter.
Response: Comment not incorporated. Reasonable acceptance criteria for the pH
sensor are necessary. The Expert Committee determined that the values for the slope
(90-105%) and offset (0.5 pH units) represent highly tolerant criteria.
Operation
Comment Summary #16: The commenter requested stating to record both the pH and
the temperature of the sample in situations where it is not practical to measure at 25⁰C.
Response: Comment incorporated.
General Chapter/Sections:
<1115> Bioburden Control in Nonsterile Drug
Substances and Products
Expert Committee:
General Chapters—Microbiology
No. of Commenters:
9
Comment Summary #1: The commenter suggested adding prevention of microbial
ingress as an additional consideration for product quality.
Response: Comment incorporated.
Comment Summary #2: The commenter suggested revising the text relating bioburden
levels lower than those recommended in <1111> to microbial toxins, as they are unlikely
to pose a risk from microbial toxins or infections.
Response: Comment incorporated.
Comment Summary #3: The commenter suggested revising or deleting the sentence,
“The products themselves are sterile or harbor a low population of microorganisms.”
This is misleading as sterile products by definition should harbor no living organisms.
Response: Comment incorporated.
22
Comment Summary #4: The commenter suggested adding a statement about
applicability to biotech drug substances, which although nonsterile, in almost all cases,
are used to manufacture sterile products.
Response: Comment not incorporated. The statement is already included within the
scope of the General Chapter; therefore, explicit mention is not needed.
Comment Summary #5: The commenter suggested removing the term “frank” to
qualify pathogenicity.
Response: Comment incorporated.
Comment Summary #6: The commenter suggested changing the term “microbial
hazard” to “microbial contamination risk” in the context of susceptibility of nonsterile
pharmaceutical products.
Response: Comment incorporated.
Comment Summary #7: The commenter indicated that the General Chapter should
also include processing steps and hold periods that could result in changes in the
bioburden in the context of susceptibility of nonsterile pharmaceutical products.
Response: Comment incorporated.
Comment Summary #8: The commenter suggested that the General Chapter should
also indicate that risk can arise where microorganism are able to proliferate to sufficient
numbers and that this is an objectionable condition.
Response: Comment incorporated.
Comment Summary #9: The commenter suggested revising the sentences that relate
to proliferation of microorganisms and the associated risks to both patient (from toxins)
and product (therapeutic properties).
Response: Comment incorporated.
Comment Summary #10: The commenter suggested including all relevant sections in
the Code of Federal Regulations relative to objectionable microorganisms/conditions.
Response: Comment incorporated.
Comment Summary #11: The commenter suggested including microbiological
attributes of in-process intermediates to the list of points to be considered to assess the
potential risk associated with nonsterile drug product manufacturing.
Response: Comment incorporated.
Comment Summary #12: The commenter suggested modifying the bullet point “age
and probable general health of intended recipients of the drug product,” to state “main
target population to which the product is delivered (e.g. Neonates, immune
compromised patients, etc.)," because it is almost impossible to track precisely for
products which are given to a high variety of patients (e.g. Ibuprofen, Aspirin).
Response: Comment incorporated. The statement was changed to, “population to
which the product is delivered.”
Comment Summary #13: The commenter suggested revising objectionable facility
conditions to include conditions that favor microbial ingress and proliferation.
Response: Comment incorporated.
Comment Summary #14: The commenter suggested deleting reference to product
recalls as it relates to factors contributing to microbial contamination and revising the
term “risk factors” to “factors,” because this does not relate to risk assessment
Response: Comment incorporated.
23
Comment Summary #16: The commenter suggested revising the term “process water”
to “water used in active ingredient manufacturing, formulation, cleaning and
housekeeping” under Water Systems and Use.
Response: Comment incorporated.
Comment Summary #17: The commenter indicated molds generally do not grow in
purified water.
Response: Comment incorporated. The sentence revised to indicate some molds can
grow.
Comment Summary #18: The commenter recommended revising or deleting the
phrase "stand in pools or puddles," because it is not clear.
Response: Comment incorporated.
Comment Summary #19: The commenter suggested inclusion of assessment for likely
contamination or proliferation risk of ingredients and excipient as important in the
reduction of microbial risk associated with these materials
Response: Comment incorporated.
Comment Summary #20: The commenter suggested including a reference to those
processes at higher risk of contamination, i.e., synthetic processes with aqueous
isolation steps or open processing, and biological processes with no downstream
chemistry or defined microbial removal step.
Response: Comment incorporated.
Comment Summary #21: The commenter suggested clarifying the term
“compounding” in the context of its use.
Response: Comment incorporated.
Comment Summary #22: The commenter suggested clarifying the phrase "labeled
with respect to microbiological status."
Response: Comment incorporated.
Comment Summary #23: The commenter indicated that the sentence that refers to
method suitability is confusing and should be deleted.
Response: Comment incorporated
Comment Summary #24: The commenter suggested defining or replacing the less
commonly term “Modern Microbiological Methods” with a more commonly used
terminology.
Response: Comment incorporated. The term was replaced with the term “Alternate
Microbiological Methods.”
Comment Summary #25: The commenter indicated that the sentence that refers to the
quality of gowns is unclear and needs clarification
Response: Comment incorporated.
Comment Summary #26: The commenter indicated that while equivalence may be of
little relevance in the context of usage of alternate methods, it is important that test
methods deliver valid and meaningful results.
Response: Comment incorporated.
Comment Summary #27: The commenter suggested revising the term “intensity” with
“frequency” in the context of sampling sites for monitoring.
Response: Comment incorporated.
Comment Summary #28: The commenter suggested replacing the phrase
microbiological “contamination potential” with microbiological “contamination risk.”
24
Response: Comment incorporated.
Comment Summary #29: The commenter suggested inclusion of facility design in risk
analysis.
Response: Comment incorporated.
General Chapter/Section(s):
<1151> Pharmaceutical Dosage Forms/
Multiple Sections
Expert Committee:
General Chapters—Dosage Forms
No. of Commenters:
2
Comment Summary #1: The commenter indicated that dose uniformity can be
demonstrated by other appropriate assays in addition to a chemical assay.
Response: Comment incorporated.
Comment Summary #2: The commenter requested deletion of the proposed change to
the definition of a capsule as possibly having drug coating on the capsule shell.
Response: Comment not incorporated. The Expert Committee found that a capsule
may have a drug as a coating.
Expert Committee-Initiated Change #1: The subsection under specific dosage forms
giving typical information on preparation or manufacture will be uniformly named as
Preparation. The Expert Committee finds the term preparation to be more general than
manufacture and will use it for the title of these subsections. Changes were made under
Lozenges and Ointments, both of which can be produced (prepared) by a pharmacist.
General Chapter/Section(s):
<1181> Scanning Electron Microscopy
Expert Committee:
General Chapters—Physical Analysis
No. of Commenters:
2
Comment # 1: The commenter requested adding a recommendation to use traceable
reference standards as a verification that the system is functioning properly in the X-Ray
Generation and Elemental Compositional Analysis section.
Response: Comment incorporated.
Comment # 2: The commenter indicated that Figure 4. Decision Tree for SEM Sample
Preparation would be easier to read if it was clearer and larger.
Response: Comment incorporated.
Comment # 3: The commenter suggested that in Figure 2. Interaction Diagram, the
letter “X” be used instead of “XRE,” which is the abbreviation used in the table prior to
this diagram. In addition, the commenter suggested defining the abbreviation “PE” used
in the diagram and labeling the greyed out areas under the surface of the sample.
Response: Comment incorporated.
Comment # 4: The commenter indicated that the statement “Crystalline particles can
be transparent to the electron beam” in the Shape analysis sub-section is problematic,
because many things are transparent and transparency may be increased if the
molecular weight is very similar to the background stub.
Response: Comment incorporated.
Comment # 5: The commenter indicated that the reference to Figure 1 under Sample
Preparation is incorrect, because there is no example of a sample stub in this version of
the General Chapter.
Response: Comment incorporated. The reference was deleted.
25
General Chapter/Sections:
<1229.6> Liquid Phase Sterilization
Expert Committee:
General Chapters—Microbiology
No. of Commenters:
6
Comment Summary #1: The commenter suggested clarifying the scope of the General
Chapter and providing examples to indicate if this chapter is about liquid chemical
sterilants, equipment for processing, or something else.
Response: Comment not incorporated. This General Chapter is part of a series of
chapters on sterilization processes using different technologies. There is no need for a
specific scope for this General Chapter.
Comment Summary #2: The commenter suggested deleting the sentence that
indicates that chemical agents are capable of destroying bacteria and fungi, including
both vegetative cells and spores in a quantitative fashion.
Response: Comment not incorporated. References were added from literature to
support the statement.
Comment Summary #3: The commenter suggested simplifying the statement which
indicates that in chemical sterilization it is customary to include the agent’s removal in
the overall process and also avoid recontamination.
Response: Comment incorporated.
Comment Summary #4: The commenter suggested revising the statement on the
sterilizing property of liquid chemicals to indicate or emphasize that this occurs in
aqueous solutions.
Response: Comment incorporated.
Comment Summary #5: The commenter suggested removing the examples of both
glutaraldhyde and formaldehyde, because these are not appropriate for use in the
pharmaceutical industry.
Response: Comment not incorporated. The Expert Committee indicated that these
agents are still used. This document only addresses the scientific aspects of
sterilization and the majority of these agents are highly toxic to humans.
Comment Summary #6: The commenter suggested deleting the statement that
indicates adequate humidity in sterilization is assured by use in aqueous solution, since
this is obvious.
Response: Comment incorporated.
Comment Summary #7: The commenter suggested revising the statement about other
factors that affect sporicidal activity by replacing the term “sporicidal” with “antibacterial.”
Response: Comment incorporated.
Comment Summary #8: The commenter stated that the statement about the choice of
biological indicators is too broad and suggested providing references from literature.
Response: Comment not incorporated. The document identifies two different Bacilli as
possible biological indicators.
Comment Summary #9: The commenter suggested adding contact time to the list of
variables for liquid chemical sterilants.
Response: Comment incorporated.
Comment Summary #10: The commenter suggested adding container closure
integrity to the list of factors to be considered by the manufacturer when selecting the
appropriate liquid chemical sterilant.
26
Response: Comment incorporated.
Comment Summary #11: The commenter suggested revising wording to indicate that
the half cycle approach supports a theoretical reduction of the biological indicators to at
least 10-6.
Response: Comment incorporated.
Comment Summary #12: The commenter suggested deleting Figure 2, because it I
unclear/confusing.
Response: Comment incorporated.
Comment Summary #13: The commenter suggested clarifying that penetration of
sterilant into needle lumens, closely fitted parts, and porous materials should be
confirmed.
Response: Comment incorporated.
Comment Summary #14: The commenter suggested revising the section on Biological
Indicators to suggest that manufacturers place indicators within loads at locations based
on risk assessment, rather than visual examination.
Response: Comment not incorporated. The Expert Committee will consider future
revisions to the General Chapter upon the receipt of the necessary supporting data.
Comment Summary #15: The commenter suggested clarifying which of the criteria in
routine process control applies to liquid chemical sterilization, because there is no FDA
guideline on this topic.
Response: Comment not incorporated. The routine process controls are universal for
all methods.
General Chapter/Section(s):
<1240> Virus Testing of Human Plasma for Further
Manufacture/Multiple Sections
Expert Committee(s):
General Chapters—Biological Analysis
No. of Commenters:
1
Comment Summary #1: The commenter requested that the General Chapter also
include testing for Syphilis, Chagas, Dengue, and similar categories of diseases caused
by bacteria, spirochetes, or parasites on plasma for further manufacture.
Response: Comment not incorporated. This General Chapter focuses on virus testing
and the Expert Committee determined that the requested additions were beyond the
scope.
Introduction
Comment Summary #2: The commenter requested adding a reference to General
Chapter <1180> after the bulleted list item describing manufacturers' strategies to
minimize the risk of virus transmission by plasma-derived products.
Response: Comment incorporated.
Comment Summary #3: The commenter requested adding the underlined text to the
sentence: "Virus transmission is a major public safety concern, because infections with
these highly pathogenic viruses typically progress to chronicity.”
Response: Comment incorporated.
Comment Summary #4: The commenter requested modifying the sentence with the
underlined text: "Other permanent or temporary donor-deferral criteria are in place to
avoid donations from potentially infected donors based on the epidemiological
27
surveillance of a country, or region or donor population for transfusion-transmissible
infections relevant to the safety of blood components.”
Response: Comment incorporated.
Comment Summary #5: The commenter requested clarifying the sentence that states,
“such as anti-HCV or anti-HIV antibodies” to specify that anti-HIV testing is for both HIV1 and HIV-2.
Response: Comment incorporated.
Comment Summary #6: The commenter requested adding the underlined text to the
sentence: "There is a finite time period, known as the window period, between the
infection of a donor and the time at...”
Response: Comment incorporated.
Comment Summary #7: The commenter requested adding the sentence: "The
recommended limit for viral load of B19V DNA in the manufacturing plasma pool should
not exceed 104 IU/mL (see FDA Guidance for industry cited in the Appendix).”
Response: Comment not incorporated. This information is already discussed earlier in
the text.
Comment Summary #8: The commenter requested adding the underlined text to the
sentence, "Testing of the plasma donations, at the individual or minipool level, and
the fractionation pools are two of the elements that manufacturers put into place to
maintain the safety margins of these products.”
Response: Comment incorporated.
Comment Summary #9: The commenter requested adding the underlined text to the
sentence, "The high sensitivity of NAT tests also allows earlier virus detection
compared to an antigen- or antibody-based test, thereby reducing the average length of
the window period donations.”
Response: Comment incorporated.
Comment Summary #10: The commenter requested adding the underlined text to the
sentence, "Nevertheless, manufacturing of plasma-derived products also includes
dedicated steps designed solely to inactivate (e.g., by solvent-detergent treatment) or
remove (e.g., by virus filtration) potential viral contaminants”
Response: Comment incorporated.
Introduction and Appendix
Comment Summary #11: The commenter requested adding the reference “Adherence
to Good Manufacturing Practices at all levels of the production process as a strategy to
reduce risk of virus transmission (see GAO-HEHS-98-205, 21 CFR Part 606, and WHO
Technical Report Series 941 cited in the Appendix)” to the bulleted list in the
Introduction and adding these new references to the Appendix.
Response: Comment incorporated.
Rationale for Virus Testing Of Plasma for Further Manufacture
Comment Summary #12: The commenter requested adding the underlined text and a
new reference to the Appendix in the sentence, "Instead, in-process NAT testing is
performed done to interdict high-titer donations and thereby limit the B19V load in the
manufacturing pool (see EMEA/CPMP/BWP/5180/03 cited in the Appendix).”
28
Response: Comment partially incorporated. The term “NAT" was added, but the Expert
Committee did not think the underlined text benefited the General Chapter and the
requested reference is sufficiently covered in other parts of the General Chapter.
Comment Summary #13: The commenter requested adding the underlined text to the
sentence, "The B19V neutralizing antibodies present in a plasma pool and the validated
virus reduction steps included in the manufacturing process ensure...”
Response: Comment incorporated.
Comment Summary #14: The commenter requested adding the underlined text to the
sentence, "However, in the United States, the Food and Drug Administration (FDA)
recommends WNV NAT testing for blood and blood components for transfusion
because of the epidemiological situation and the risk of WNV transmission by blood
components (see FDA Guidance for industry cited in the Appendix).” and the new
reference to the Appendix: “FDA Guidance for industry: use of nucleic acid tests to
reduce the risk of transmission of West Nile Virus from donors of whole blood and blood
components intended for transfusion.”
Response: Comment incorporated.
Regulatory Environment
Comment Summary #15: The commenter requested adding the underlined text to the
sentence, "For HIV and HCV, the procedure includes not only the quarantine and
destruction of unused, previously donated units from an infected donor, but also the
further testing of the donor and notification of the recipients of the blood and blood
components (21 CFR 610.47-48).”
Response: Comment incorporated.
Comment Summary #16: The commenter requested revising the text as shown,
"Additional tests and specifications for plasma for further manufacture have been
developed as a voluntary industrial standard by part of the Plasma Productein
Therapeutics Association (PPTA) Voluntary Standards Program. The PPTA Quality
Standards of or Excellence, Assurance, and Leadership (QSEAL) includes
requirements for additional routine testing of blood and plasma donations or plasma
pools for HCV RNA, HIV RNA, HBV DNA, HAV RNA, and B19V DNA.”
Response: Comment incorporated.
Table 3
Comment Summary #17: The commenter requested adding the underlined text to the
second column of the table, "Required with a manufacturing pool limit of ≤ 104 IU/mL
B19V DNA” and in column 3 for B19V: “Required for specific products (anti-D
immunoglobulin and pooled S/D-treated plasma); a manufacturing pool limit of B19V
DNA ≤ 104 IU/mL is required. This limit is voluntarily implemented by most plasma
fractionators for all products.”
Response: Comment incorporated.
Conclusions
Comment Summary #17: The commenter requested adding the underlined text to the
second column of the table, "Both manufacturers and regulators face continuing
29
challenges, because of the emergence of new blood-borne viruses, mutants, and
variants of existing viruses not detected by current serological/NAT technology.”
Response: Comment incorporated.
General Chapter/Section(s):
Expert Committee(s):
No. of Commenters:
<1234> Vaccines for Human Use-- Polysaccharide
and Glycoconjugate Vaccines/Multiple Sections
General Chapters—Biological Analysis
1
Key Quality Parameters for Activated Intermediates, Degree of Activation of
Activated Polysaccharides subsection
Comment Summary #1: The commenter requested a correction to the sentence,
“Residual unconjugated linker that could interfere with subsequent steps should be
controlled via measurement or process validation,” because the testing is not
appropriate for this intermediate prior to conjugation.
Response: Comment incorporated. The sentence was omitted and replaced with the
sentence, "In cases where the activated polysaccharide is conjugated without isolation,
consistency in the degree of polysaccharide activation may also be demonstrated as
part of process validation or reflected by characteristics of the final conjugate bulk."
Key Quality Parameters for Activated Intermediates, Degree of Activation of
Activated Carrier Protein subsection
Comment Summary #2: The commenter requested a correction to the sentence, "In a
validated process where production consistency has been established, and depending
on the conjugation chemistry used and the results of clinical trials, testing may be used
as an in-process control.” because the testing is not appropriate for this intermediate
prior to conjugation.
Response: Comment incorporated. The sentence was omitted and replaced with the
sentence, "Depending on the conjugation chemistry used (i.e., immediate conjugation
after activation), consistency in degree of carrier protein activation may also be
demonstrated as part of process validation or reflected by characteristics of the final
conjugate bulk.
Expert Committee-Initiated Change #1: Table 1 was corrected by removing the X's in
the hexosamine column for Men A, Y, and W, and removing the X’s in the total sugar
column for Men C.
Expert Committee-Initiated Change #2: Table 2's glycosylation nomenclature was
updated from NeuNAc to Neu5Ac for consistency and to harmonize with General
Chapter <1084>'s terminology.
30
General Chapter/Section(s):
Expert Committee(s):
No. of Commenters:
<1736> Applications of Mass Spectrometry/Multiple
Sections
General Chapters—Chemical Analysis
7
Section 1. Introduction
Comment Summary #1: The commenter indicated that mass spectrometers measure
mass and not weight.
Response: Comment incorporated
Comment Summary #2: The commenter suggested replacing “(Identification test)” with
structural elucidation.
Response: Comment not incorporated. The Expert Committee will consider further
revisions to the monograph upon the receipt of supporting data.
Comment Summary #3: The commenter suggested that comparison of a mass
spectrometer to an analytical balance is misleading.
Response: Comment incorporated. The sentence was removed.
Comment Summary #4: The commenter suggested that the sentence “Molecular
weight thus can become a surrogate for confirmation…” does not deliver adequate
certainty unless minimally accurate mass is employed.
Response: Comment not incorporated. The Expert Committee determined that the
passage does not specify that molecular mass is the only identification criteria.
Section 2. Mass Spectrometers
Comment Summary #5: The commenter suggested revising the sentence:
“…represented in a graphic representation of mass-to-charge ratio (m/z) versus
intensity” to change the order of intensity and mass-to-charge ratio.
Response: Comment not incorporated. The Expert Committee determined that the
change would not enhance the meaning and understanding of the General Chapter.
Comment Summary #6: The commenter suggested deletion of “from low mass ions to
high” in the sentence: “Regardless of type, the mass analyzer separates ions according
to the m/z, from low mass ions to high.”
Response: Comment incorporated.
Comment Summary #7: The commenter suggested deletion of the phrase, “ … a
survey of ions generated in the ion source” from the sentence “The mass analyzer
continuously acquires data across a predefined range of masses to generate the
resulting mass spectra, a survey of ions generated in the ion source.”
Response: Comment incorporated.
Comment Summary #8: The commenter suggested deleting sample preparation and
chromatography from the processes typical of MS measurements as they are specific to
liquid or gas chromatographic procedures and not mass spectrometry procedures.
Response: Comment partially incorporated. The Expert Committee determined that
this statement is appropriate in the Overview section and that the edits made to the
Layout section were sufficient to address this comment.
Comment Summary #9: The commenter suggested that fragmentation ions generated
during an MS/MS experiment be included as a source of ions in the Overview.
31
Response: Comment not incorporated. The Expert Committee determined that
sufficient explanation of ion fragmentation is contained in the General Layout sections.
Comment Summary #10: The commenter suggested editing the following sentence
“.mass (molecular weight assignment) of each of the 10 components” to indicate that if
the components have different molecular weights, then chromatographic separation is
not necessary.
Response: Comment incorporated. The sentence was changed to read, “… mass-tocharge of each of the 10 components”
Comment Summary #11: The commenter indicated that all mass spectrometers need
a sample introduction technique.
Response: Comment incorporated. Sample introduction technique bullet was added to
the General Layout section.
Comment Summary #12: The commenter suggested editing the sentence to “and is
represented in a graphic representation of intensity versus mass-to-charge ratio (m/z).”
instead of “…mass-to-charge (m/z) versus intensity.”
Response: Comment not incorporated. Because?
Comment Summary #13: The commenter suggested that the word “measure” be used
in place of “count” in the phrase: “A detector to count the ions.”
Response: Comment incorporated.
Comment Summary #14: The commenter suggested that Figure 1 be amended to
remove Autosampler segment, by replacing “Collection” with “Detection” over the UV
spectrum, “fractionation” with “separation” over HPLC, and “Spectroscopic Analysis”
with “detection (and fragmention).”
Response: Comment incorporated. The Expert Committee also replaced
“Spectroscopic Analysis” with “Mass Spectrometric Analysis.”
Comment Summary #15: The commenters indicated that mass spectrometers
measure mass-to-charge and not molecule weight.
Response: Comments incorporated. The use of the term molecular weight was
replaced in several places in the chapter with mass-to-charge or molecular mass as
appropriate.
Comment Summary #16: The commenter suggested that the statement “A system with
two mass analyzers in sequence” does not allow for tandem in time (ion traps).
Response: Comment incorporated. The sentence was edited to state, “A system
capable of carrying out two sequential m/z analysis events.”
Comment Summary #17: The commenter suggested broadening the definition of
tandem mass spectrometers in Section 2.2.2
Response: Comment incorporated.
Comment Summary #18: The commenter suggested that section Direct Introduction
include descriptions of the many ambient ionization techniques.
Response: Comment not incorporated. The Expert Committee may consider including
this suggestion in future revisions of the General Chapter.
Comment Summary #19: The commenter indicated that the section title contains the
improper case for the letter n, in the abbreviation MSn.
Response: Comment incorporated.
32
Comment Summary #20: The commenter suggested revising the definition in the
HPLC chromatographic introduction technique section to allow for non-volatile
components to be analyzed.
Response: Comment incorporated. The Expert Committee edited the sentence to
more broadly describe analytes capable of HPLC analysis. “HPLC procedures are
preferred for non-volatile and thermally labile analytes, but are suitable for use with any
analyte that is readily ionizable in a solution environment with the appropriate chemical
modifiers.”
Comment Summary #21: The commenter indicated that Section 2.4.1 should be
revised, because proteins and peptides are typically protonated with more than one
proton.
Response: Comment incorporated.
Comment Summary #22: The commenter suggested adding the sentence,
“Additionally, fragmentation patterns have been extensively studied for electron
ionization and can help determine structure of unknown compounds.” to Section 2.5.1.
Response: Comment incorporated.
Comment Summary #23: The commenter suggested adding the sentence, “CI is very
useful for reactive and unstable compounds where a molecular mass determination is
desired” to Section 2.5.2.
Response: Comment incorporated.
Comment Summary #24: The commenter indicated that chemical ionization is
dependent on both analyte and reagent gas.
Response: Comment not incorporated. The Expert Committee determined that this
Section does not contradict this comment.
Comment Summary #25: The commenter indicated that the term “protonated
molecule” should be used instead of “protonated molecular ion” throughout the General
Chapter.
Response: Comment incorporated.
Comment Summary #26: The commenter requested that the schemes in Section 2.5.2
be corrected to have a consistent format.
Response: Comment incorporated. The schemes were formatted to be consistent.
Comment Summary #27: The commenter requested that the sub-section Electrospray
Ionization be moved to a subsection under Section 2.5.3 Atmospheric Pressure
Ionization.
Response: Comment incorporated.
Comment Summary #28: The commenter suggested moving Table 1 out of the
paragraph and placing it at the end of the document or another unobtrusive location.
Response: Comment not incorporated. Table 1 is located in a location close to the first
reference, as is conventional.
Comment Summary #29: The commenter suggested splitting Section 3.3 Ion Traps
and Ion Cyclotron Resonance into two sections.
Response: Comment not incorporated. The Expert Committee determined that the
change would not enhance understanding of the General Chapter.
Expert Committee-Initiated Change #1: The Section titled Atmospheric Pressure
Chemical Ionization was moved to become a subsection under Section 2.5.3
Atmospheric Pressure Ionization.
33
Section 4. MS/MS and MSn Spectrometers
Comment Summary #30: The commenter suggested changing the nomenclature to
MS/MS and/or MSn in the section titles and text.
Response: Comment incorporated.
Comment Summary #31: The commenter suggested revising the caption for Figure 4C
to read “The scan results in a spectrum that contains all ions…” instead of “molecular
ion.”
Response: Comment incorporated. The Expert Committee modified this proposal to
read “precursor ions.”
Comment Summary #32: The commenter suggested removing the explanation of
SWIFT in Section 4.1.5 Fourier-Transform Ion Cyclotron Resonance, because the
proposed explanation is inadequate.
Response: Comment incorporated.
Comment Summary #33: The commenter suggested that the General Chapter cover
OrbitrapTM technology.
Response: Comment partially incorporated. Orbital trapping mass spectrometers have
been included in the list of some possible configurations, but trademarked brand names
were avoided.
Comment Summary #34: The commenter suggested changing the phrase “scan
mode” to “acquisition mode” in Section 4.2.2.4 MSn, because FT-ICR spectrometers are
not scanning instruments.
Response: Comment incorporated.
Section 5. Qualitative Analysis
Comment Summary #35: The commenter indicated that it was unclear whether subsection 5.1.1 Resolution defined resolution or mass resolving power.
Response: Comment partially incorporated. The sub-section title was changed to 5.1.1
Mass Resolution. The Expert Committee determined that a more detailed definition of
resolution and mass resolving power was not necessary to give the reader an adequate
perspective.
Comment Summary #36: The commenter suggested clarifying the sentence, “HRMS
can be performed with a number of different technologies, including TOF–MS, as well
as orbital-trapping MS and ion cyclotron resonance MS use Fourier transformation to
process the raw data,’ in section 5.1.1.2 High resolution, to reflect that the latter two
techniques use Fourier transformation and not TOF-MS.
Response: Comment incorporated. The sentence was changed to state, “HRMS can
be performed with a number of different technologies, including TOF–MS, as well as
orbital-trapping MS and ion cyclotron resonance MS, where the latter two approaches
utilize Fourier transformation to process the raw data.”
Comment Summary #37: The commenter indicated that the sentence, “The mass of a
compound often is represented by the peak observed at highest m/z in the spectrum.” in
sub-section 5.2 Interpretation of Mass Spectra is not true in many instances.
Response: Comment incorporated. The sentence was deleted.
34
Comment Summary #38: The commenter indicated that the statement “M+H and M-H
often appear most prominent” is too general and not always true. The ions that appear
are chemistry and ion source condition dependent.
Response: Comment incorporated. The sentence is revised to state that the M+H and
M-H often appear as a prominent peak.
Comment Summary #39: The commenter suggested that the acronym mMRA be
defined in the phrase “With the development of complete databases of many genes,
mMRA, and proteins…”
Response: Comment partially incorporated. The acronym mMRA was a misspelling of
mRNA. The Expert Committee determined that the acronym should be replaced with
the word “transcripts,” which makes the context of the sentence more broadly applicable
and clear.
Comment Summary #40: The commenter indicated that there is no need for multiple
protease digestions if one enzyme digest covers all sequence.
Response: Comment not incorporated. The Expert Committee determined that the
section does not contradict the comment.
Expert Committee-Initiated Change #2: The sub-script 1 on 12C and 34S was
removed, because it was not necessary. When a single heavy isotope is present, the
sentence may read, “The major contributor to the A + 1 peak results from the
occurrence of versions of the molecule containing 13C, and the major contributor to the
A + 2 peak, is naturally occurring 34S.
Expert Committee-Initiated Change #3: Figure 6A. peptide fragmentation
nomenclature was replaced, but there were no other changes.
Section 6. Quantitative Analysis
Comment Summary #41: The commenter suggested including a discussion regarding
the use of quantitative analysis of potential genotoxic impurities.
Response: Comment not incorporated. Potential genotoxic impurities are a case study
within the broader context of this section. The Expert Committee determined that
specific attention to such analysis was not necessary.
Section 7. Drug Product Authentication and Contamination Detection
Comment Summary #42: The commenter indicated the standard MS experiment
described in sub-section 7.1.1 Identification was inadequate to provide certainty and
that accurate mass and MS/MS experiments were both needed.
Response: Comment partially incorporated. The sub-section title was changed to
Identification and/or Verification of the Active Ingredient. The Expert Committee
determined that a more thorough explanation of the types of experiments needed for
certainty were beyond the scope of this document, because many scenarios are
possible and are case dependent.
Expert Committee-Initiated Change #4: Figure 9 was converted to black and white,
because some symbols do not appear in the color version in the Pharmacopeial Forum.
No changes were made to the data or caption.
35
General
Comment Summary #43: The commenter requested that General Chapter <736>
Mass Spectrometry (instrument qualification and method validation) be combined with
General Chapter <1736> Applications of Mass Spectrometry (theory, instrumentation,
and practices), because the information in both chapters is applicable to the Mass
Spectrometry.
Response: Comment not incorporated. The Expert Committee followed the strategy
developed and published in a Stimuli Article “An Alignment of Concepts and Content
across the Spectroscopy General Chapters in the United States Pharmacopeia–
National Formulary (USP–NF)” Pharmacopeia Forum 40(1) [Jan.–Feb. 2013].
Comment Summary #44: The commenter indicated that General Chapter <1736>
Applications of Mass Spectrometry is very detailed and proposed several different
approaches for organization of the information.
Response: Comment not incorporated. The Expert Committee followed the current
USP format for a general information chapter.
Comment Summary #45: The commenter indicated that with the advent of higher
resolution accurate mass instruments, potential structural formulas can now be
generated for molecular ions and fragments.
Response: Comment not incorporated. The Expert Committee determined that the
contents of the General Chapter do not contradict this comment.
Comment Summary #46: The commenter indicated that the General Chapter is
specific to small molecule drugs and does not cover biologics. The commenter
proposed options for handling the interpretation of spectra for these two very different
classes.
Response: Comment not incorporated. The Expert Committee determined that the
current scope is sufficient but will reconsider the comment with future revisions.
Comment Summary #47: The commenter indicated that the placement of Table 1 in
the text was a distraction and did not add value to the immediate discussion.
Response: Comment not incorporated. The placement of Table 1 was not presented
well due to the Pharmacopeial Forum format. In the USP–NF format, the Table
placement is appropriate.
General Chapter/Section(s):
<2250> Detection of Irradiated Dietary
Supplements/ Multiple Sections
Expert Committee:
General Chapters—Chemical Analysis
No. of Commenters:
2
Comment Summary # 1: The commenter requested that the phrase “except for
disinfestation of arthropods using 1 kGy (21 CFR 179.26),” be deleted from the
Introduction.
Response: Comment incorporated.
Comment Summary # 2: The commenter mentioned that some products like soy
isoflavones have high photostimulated luminescence (PSL) signal which might be
misinterpreted as positive.
Response: Comment not incorporated. This situation is covered in the General Chapter
by stating that (1) PSL is a simple preliminary screening method to detect irradiation
and (2) samples classified as intermediate based on PSL signals will require further
36
investigation by the TL method to determine their irradiation status. The Expert
Committee will consider future revisions to the General Chapter upon the receipt of
necessary supporting data.
Monograph/Section(s):
L-Alanyl-L-Glutamine/Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
Expert Committee-Initiated Change #1: The Identification C test was removed,
because it was not suitable for identification purposes.
Monograph/ Section(s):
Azelastine Hydrochloride/Multiple sections
Expert Committee:
Monographs—Small Molecules 4
No. of Commenters:
3
Comment Summary #1: The commenter requested revising the Assay to include
additional instructions to prevent overheating in the reaction medium.
Response: Comment incorporated.
Comment Summary #2: The commenter requested widening the limit for the test for
Residue on Ignition from NMT 0.1% to NMT 0.2% to reflect approved acceptance
criteria.
Response: Comment incorporated.
Comment Summary #3: The commenter requested widening the limit in the test for
Heavy Metals from NMT 10 ppm to NMT 20 ppm to reflect approved acceptance
criteria.
Response: Comment incorporated.
Comment Summary #4: The commenter requested revising the names of
“benzohydrazide” and “chlorophenylacetyl benzoic acid” to “Azelastine Related
Compound A” and “Azelastine Related Compound C,” respectively, to make them
consistent with the labels used in the Ph.Eur. monograph.
Response: Comment not incorporated. The proposed names are consistent with
current USP format; the use of the term “Related Compound” is reserved for materials
that are available as USP Reference Standards.
Comment Summary #5: The commenter requested widening the limit in the test for
Loss on Drying from NMT 0.5% to NMT 1.0% to reflect approved acceptance criteria.
Response: Comment incorporated.
Comment Summary #6: The commenter requested eliminating the test for Acidity or
Alkalinity, because the Organic Impurities test quantifies acidic and alkaline impurities.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Monograph/Section(s):
Borage Seed Oil/ Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
Expert Committee-Initiated Change #1: The monograph title was changed from
“Borage Oil” to “Borage Seed Oil” to specify the plant part from which the oil is obtained.
Expert Committee-Initiated Change #2: The Identification B test was removed,
because the cross-referenced new General Chapter <202> Identification of Fixed Oils
by Thin Layer Chromatography is still in development.
37
Expert Committee-Initiated Change #3: The USP Borage Seed Oil RS requirement
was removed, because it is associated with the removed Identification B test.
Monograph/ Section(s):
Brompheniramine Maleate/Organic impurities
Expert Committee:
Monographs—Small Molecules 4
No. of Commenters:
1
Comment Summary #1: The commenter requested tightening the total impurity limits
in the test for Organic Impurities to reflect approved acceptance criteria.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Monograph/Sections:
Carbamazepine Extended-Release Tablets/Assay
Expert Committee:
Monographs—Small Molecules 4
Expert Committee-Initiated change: The preparation of Sample stock solution B is
corrected to refer to Sample stock solution A rather than to Standard stock solution.
Monograph/Section:
Dorzolamide Hydrochloride and Timolol Maleate
Ophthalmic Solution/ Multiple Sections
Expert Committee:
Monographs—Small Molecules 3
No. of Commenters:
2
Comment Summary #1: The commenter requested widening the limits in the test for
pH to reflect approved acceptance criteria.
Response: Comment incorporated. The pH range was widened from 5.5-5.8 to 5.4-5.9.
Comment Summary #2: The commenter requested widening the limit for timolol
impurity B from NMT 0.5% to NMT 1.0%, and the limit for unspecified impurities from
NMT 0.5% to NMT 0.6% in the test for Organic impurities: Timolol Maleate based on
approved acceptance criteria.
Response: Comment incorporated.
Comment Summary #3: The commenter requested revising the Organic impurities
procedure to include the limits for two additional impurities.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Comment Summary #4: Commenter requested revising the dorzolamide concentration
of the Standard solution in the test for Organic impurities: Dorzolamide Hydrochloride to
facilitate the determination of unspecified impurities.
Response: Comment not incorporated. The unspecified impurities are calculated by
area normalization, and the concentration of the Standard solution does not affect their
quantitation.
Comment Summary #5: The commenter requested revising the test for Organic
impurities: Dorzolamide Hydrochloride to include relative response factors for the
calculation of dorzolamide related compounds B and D.
Response: Comment not incorporated. The procedure does not require a relative
response factors for these impurities because USP Dorzolamide Related Compounds B
and D are used quantitatively in the proposed procedure.
Comment Summary #6: The commenter suggested adding the relative retention time
of timolol in Table 2 in the test for Organic impurities: Dorzolamide Hydrochloride.
38
Response: Comment not incorporated. The Expert Committee determined that timolol
peak is not observed in the procedure.
Monograph/Section:
Enzacamene /Identification B
Expert Committee:
Monographs—Small Molecules 3
Expert Committee-Initiated Change #1: The acceptance criterion for the ratio of
absorptivities was deleted. The Expert Committee determined that the maxima and
minima agreements between Standard solution and Sample solution provide sufficient
information to identify enzacamene.
Monograph/Section(s):
Evening Primrose Oil/Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
Expert Committee-Initiated Change #1: The Identification B test was removed,
because the cross-referenced new General Chapter <202> Identification of Fixed Oils
by Thin Layer Chromatography is still in development.
Expert Committee-Initiated Change #2: The USP Evening Primrose Oil RS
requirement was removed, because it is associated with the removed Identification B
test.
Monograph/Section(s):
Flax Seed Oil/Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
No. of Commenters:
1
Comment Summary #1: The commenter suggested increasing the upper limit of Iodine
Value from 165 to 200.
Response: Comment not incorporated. The Expert Committee will consider further
revisions to the monograph upon receipt of supporting data.
Expert Committee-Initiated Change #1: The monograph title was changed from Flax
Oil to Flax Seed Oil to specify the plant part from which the oil is obtained.
Monograph/Section(s):
Flunixin Meglumine/Multiple sections
Expert Committee:
Monographs—Small Molecules 3
No. of Commenters:
1
Comment Summary #1: The commenter requested aligning the concentration of
flunixin related compound C in the test for Organic Impurities with that of impurity C in
the test for Related substances in the corresponding Ph.Eur. monograph.
Response: Comment not incorporated. The Expert Committee determined that the
concentration of related compound C in the PF 39(4) proposal is appropriate for its
intended application.
Comment Summary #2: The commenter requested adding a relative response factor
for the quantitation of related compound C in the test for Organic impurities.
Response: Comment not incorporated. The procedure does not require a relative
response factor for related compound C, because USP Related Compound C RS is
used quantitatively in the proposed procedure.
Comment Summary #3: The commenter requested aligning the resolution
requirement with that in the test for Related substances in the corresponding Ph.Eur.
monograph.
39
Response: Comment not incorporated. The Expert Committee determined the
resolution limit in the PF 39(4) proposal, which is supported by validation data, is
appropriate for its intended use.
Comment Summary #4: The commenter requested alignment of the sample
concentration and temperature used in the test for Specific Rotation with that in Specific
Optical Rotation test in the corresponding Ph.Eur. monograph.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Comment Summary #5: The commenter requested tightening the limit in the test for
Residue on Ignition from NMT 0.2% to NMT 0.1% to align with the Sulfated Ash limit in
the corresponding Ph.Eur. monograph.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Monograph/Section(s):
Ganoderma Lucidum Fruiting Body/Identification
Expert Committee:
Monographs—Dietary Supplements
No. of Commenters:
1
Comment Summary #1: The commenter indicated that in the Identification B by HPLC,
Ganoderenic acid A was listed within the acceptance criteria, although absent from
Table 3 listing Relative Retention Times and Relative Response Factors.
Response: Comment incorporated. The reference to Ganoderenic acid A was
removed from the Acceptance Criteria.
Monograph/Section(s):
Ganoderma Lucidum Fruiting Body Powder/
Identification
Expert Committee:
Monographs—Dietary Supplements
No. of Commenters:
1
Comment Summary #1: The commenter noted that in the Identification B by HPLC,
Ganoderenic acid A was listed within the acceptance criteria, although absent from
Table 3 listing Relative Retention Times and Relative Response Factors.
Response: Comment incorporated. The reference to Ganoderenic acid A was
removed from the Acceptance Criteria.
Monograph/Section(s):
Glycyl-L-Glutamine/Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
Expert Committee-Initiated Change #1: The Identification C test was removed,
because it was not suitable for identification purposes.
Monograph/Section(s):
Glycyl-L-Tyrosine/Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
Expert Committee-Initiated Change #1: The Identification C test was removed,
because it was not suitable for identification purposes.
40
Monograph/Sections:
Hydroxyzine Hydrochloride/Multiple sections
Expert Committee:
Monographs—Small Molecules 4
No. of Commenters:
2
Comment Summary #1: The commenter requested retaining the test for Loss on
Drying but with the drying conditions from the corresponding European Pharmacopeia
monograph.
Response: Comment not incorporated. The Expert Committee had previously
considered the requested change and determined that the test for Water Content is
appropriate for inclusion in this monograph.
Comment Summary #2: The commenter requested adding the specified impurity 4chlorobenzophenone to the monograph based on FDA approved limits.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Monograph/Sections:
Imipramine Pamoate/Multiple sections
Expert Committee:
Monographs—Small Molecules 4
No. of Commenters:
1
Comment Summary #1: The commenter requested including a test for chloride based
on FDA approved limits.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Comment Summary #2: The commenter requested including a test for pamoic acid
content based on FDA approved limits.
Response: Comment not incorporated. The Expert Committee finds the current content
requirement for the active moiety and identification test for the pamoic acid to be
sufficient.
Monograph/Section(s): Krill Oil/Multiple Sections
Expert Committee: Monographs—Dietary Supplements
No. of Commenters: 2
Identification A
Comment Summary #1: The commenter requested the specifications of the Fatty Acid
Profile in Table 1 be modified to reflect a wider range of sources from which the krill oil
is obtained.
Response: Comment incorporated.
Content of Total Phospholipids
Comment Summary #2: The commenter requested that the purity specification of NLT
99.0% for triphenyl phosphate, the internal standard, be added to clarify the reagent
grade requirement.
Response: Comment incorporated.
Comment Summary #3: The commenter requested adding ‘1H frequency’ to the
specification of magnetic field strength to clarify the type of isotopes frequency used.
Response: Comment incorporated.
41
Monograph/Section(s):
Expert Committee:
No. of Commenters:
Krill Oil Capsules/Multiple Sections
Monographs—Dietary Supplements
2
Identification A
Comment Summary #1: The commenter requested the specifications of the Fatty Acid
Profile in Table 1 be modified to reflect a wider range of sources from which the krill oil
is obtained.
Response: Comment incorporated. The specifications for the fatty acid profile were
modified based on the additional data received.
Content of Total Phospholipids
Comment Summary #2: The commenter requested that additional clarifications be
provided for the purity of the triphenyl phosphate used for Internal standard preparation.
Response: Comment incorporated. Additional clarifications were provided.
Comment Summary #3: The commenter requested adding ‘1H frequency’ to the
specification of magnetic field strength to clarify the type of isotopes frequency used
Response: Comment incorporated. Additional clarifications were provided.
Monograph/Section(s):
Krill Oil Delayed-Release Capsules/Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
Expert Committee-Initiated Change #1: Expert Committee incorporated the
comments received for Krill Oil Capsules monograph into the Krill Oil Delayed-Release
Capsules monograph.
Monograph/Section:
Levobunolol Hydrochloride / Multiple Sections
Expert Committee:
Monographs—Small Molecules 3
Expert Committee-Initiated Change #1: The Resolution requirement in the test for
Organic Impurities was revised to indicate that the resolution is between the levobunolol
and atenolol peaks.
Expert Committee-Initiated Change #2: In Packaging and Storage the requirement for
storage at “controlled room temperature” is changed to “room temperature.”
Monograph/Section:
Levobunolol Hydrochloride Ophthalmic Solution
/Assay
Expert Committee:
Monographs—Small Molecules 3
Expert Committee-Initiated Change #1: The Relative Standard Deviation under
System suitability is widened from NMT 0.73% to NMT 1.5%.
Monograph/Sections:
Mitomycin/Organic Impurities
Expert Committee:
Monographs—Small Molecules 1
No. of Commenters:
1
Comment Summary #1: The commenter requested revising the relative response
factors for the impurities based on laboratory data.
42
Response: Comment not incorporated. The requested change is not consistent with the
validated procedure and the proposed acceptance criteria.
Monograph/Section:
Naphazoline Hydrochloride Ophthalmic Solution
/Assay
Expert Committee:
Monographs—Small Molecules 3
Expert Committee-Initiated Change #1: The Chromatographic system in the Assay is
revised to add a reference to the diode array detector to accommodate the proposed
test for Identification B. A note is added to indicate that the diode array detector should
be used to perform Identification B.
Monograph/Section(s):
Nicardipine Hydrochloride/Organic Impurities
Expert Committee(s):
Monographs—Small Molecules 2
No. of Commenters:
1
Comment Summary # 1: The commenter requested widening of the reporting
threshold in the test for Organic Impurities.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Monograph/Section:
Oxymetazoline Hydrochloride Ophthalmic Solution
/Assay
Expert Committee:
Monographs—Small Molecules 3
Expert Committee-Initiated Change #1: The Chromatographic system in the Assay is
revised to add a reference to the diode array detector to accommodate the proposed
test for Identification B. A note was added to indicate that the diode array detector
should be used to perform Identification B.
Monograph/Section(s):
Paroxetine Extended-Release Tablets/ Multiple
Sections
Expert Committee:
Monographs—Small Molecules 4
No. of Commenters:
2
Comment Summary #1: The commenter requested aligning the concentrations of the
Sample solution and Standard solution in the Assay.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Comment Summary #2: The commenter requested including stereochemical
information in the chemical name for ethoxyparoxetine.
Response: Comment incorporated.
Comment Summary #3: The commenter requested including a Dissolution procedure
and acceptance criteria.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Comment Summary #4: The commenter requested including a test for the limit of
enantiomer.
43
Response: Comment not incorporated. The stability data provided by the sponsor
shows no evidence of racemization.
General Chapter/Section(s):
Polysorbate 80/Assay
Expert Committee(s):
Monographs—Excipients
No. of Commenters:
1
Comment Summary #1: The commenter indicated that in Table 3 in Assay, the
acceptance criteria for Oleic Acid should be NLT 58.0% instead of NMT 58.0%.
Response: Comment incorporated.
Monograph/Section(s):
Rhodiola rosea /Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
No. of Commenters:
1
Comment Summary #1: The commenter noted that the volume of acetone was not
specified in the preparation of Derivatization reagent of Thin-Layer Chromatography
Test A of the Identification section.
Response: Comment incorporated. The volume of acetone, 40 mL, was included.
Expert Committee-Initiated Change #1: The USP Powdered Rhodiola rosea Extract
RS under USP Reference Standards in the Additional Requirements section was
renamed to USP Rhodiola rosea Root and Rhizome Dry Extract RS to reflect the
updated nomenclature conventions.
Monograph/Section(s):
Powdered Rhodiola rosea/Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
No. of Commenters:
1
Comment Summary #1: The commenter noted that the volume of acetone was not
specified in the preparation of Derivatization reagent of Thin-Layer Chromatography
Test A of the Identification section.
Response: Comment incorporated. The volume of acetone, 40 mL, was included.
Expert Committee-Initiated Change #1: The USP Powdered Rhodiola rosea Extract
RS under USP Reference Standards in the Additional Requirements section was
renamed to USP Rhodiola rosea Root and Rhizome Dry Extract RS to reflect the
updated nomenclature conventions.
Monograph/Section(s):
Powdered Rhodiola rosea Extract/Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
No. of Commenters:
1
Comment Summary #1: The commenter indicated that the volume of acetone was not
specified in the preparation of Derivatization reagent of Thin-Layer Chromatography
Test A of the Identification section.
Response: Comment incorporated. The volume of acetone, 40 mL, was included.
Expert Committee-Initiated Change #1: The USP Powdered Rhodiola rosea Extract
RS under USP Reference Standards in the Additional Requirements section was
renamed to USP Rhodiola rosea Root and Rhizome Dry Extract RS to reflect the
updated nomenclature conventions.
44
Monograph/Section(s):
Rhodiola rosea Tincture/Multiple Sections
Expert Committee:
Monographs—Dietary Supplements
No. of Commenters:
1
Comment Summary #1: The commenter indicated that the volume of acetone was not
specified in the preparation of Derivatization reagent of Thin-Layer Chromatography
Test A of the Identification section.
Response: Comment incorporated. The volume of acetone, 40 mL, was included.
Expert Committee-Initiated Change #1: The USP Powdered Rhodiola rosea Extract
RS under USP Reference Standards in the Additional Requirements section was
renamed to USP Rhodiola rosea Root and Rhizome Dry Extract RS to reflect the
updated nomenclature conventions.
Monograph/Section:
Risperidone /Organic Impurities
Expert Committee:
Monographs—Small Molecules 4
No. of Commenters:
2
Comment Summary #1: The commenter requested including the chemical name of
risperidone related compound G in Table 2 in the test for Organic Impurities.
Response: Comment not incorporated. The chemical name is available in the USP
Reference Standards section of the monograph.
Comment Summary #2: The commenter requested revising the test for Organic
Impurities to address a compound that is observed in the commenter’s product and
which co-elutes with 5-fluororisperidone.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Comment Summary #3: The commenter requested revising the test for Organic
Impurities to include acceptance criteria for additional compounds.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Monograph/Section:
Salmeterol Inhalation Powder/Multiple sections
Expert Committee:
Monographs—Small Molecules 4
No. of Commenters:
2
Comment Summary #1: The commenter requested including specific details of the
procedure use for Microbial Enumeration<61>.
Response: Comment not incorporated. The existing text allows the flexibility of
choosing the most appropriate procedure included in General Chapter <61>.
Comment Summary #2: The commenter requested clarifying the variables Wn and Wu
in the test for Organic Impurities.
Response: Comment incorporated.
Monograph/Section:
Sertraline Hydrochloride /Multiple sections
Expert Committee:
Monographs—Small Molecules 4
No. of Commenters:
5
Comment Summary #1: The commenter requested revising the limit for Total
Impurities in the test for Organic Impurities.
45
Response: Comment not incorporated. The Expert Committee will consider future
revisions to the monograph upon receipt of supporting data.
Comment summary #2: The commenter requested widening the Tailing Factor
requirement in the Assay from NMT 1.6 to NMT 2.0 based on supporting data.
Response: Comment incorporated.
Comment summary #3: The commenter requested increasing the concentration of the
Sample solution in the test for Organic Impurities to allow more accurate quantification
of the impurities.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Comment summary #4: The commenter requested revising Organic Impurities
Procedure 2 to improve recovery.
Response: Comment not incorporated. The Expert Committee will consider a future
revision upon receipt of supporting data.
Comment summary #5: The commenter requested including an additional
identification test.
Response: Comment not incorporated. The Expert Committee finds the current three
identification procedures to be sufficient.
Comment summary #6: The commenter requested including their procedures for
Organic impurities.
Response: Comment not incorporated. The Expert Committee determined that the
commenter’s procedures do not offer significant advantages over the proposed
procedures.
Monograph/ Sections:
Sodium Phenylbutyrate/Multiple Sections
Expert Committee:
Monographs—Small Molecules 3
Expert Committee-Initiated Change #1: The names of USP Sodium Phenylbutyrate
Related Compounds A, B, and C RS were changed to USP Phenylbutyrate Related
Compounds A, B, and C RS, respectively.
Expert Committee-Initiated Change #2: The name of the test for Limit of Sodium
Phenylbutyrate Related Compound C was revised to Limit of Phenylbutyrate Related
Compound C.
Monograph/Section:
Succinic Acid/Assay
Expert Committee(s):
MonographsExcipients
No. of Commenters:
1
Comment Summary #1: In the Assay, the commenter recommended providing detailed
information for preparation of Diluent.
Response: Comment incorporated.
Monograph/Section:
Trazodone Hydrochloride Tablets/Organic Impurities
Expert Committee:
Monographs—Small Molecules 4
No. of Commenters:
1
Comment Summary #1: The commenter requested revising the trazodone
concentrations of the System suitability solution and Standard solution in the test for
Organic Impurities to align with each other.
46
Response: Comment not incorporated. The proposed concentrations of trazodone in
the System suitability solution and Sample solution reflect supporting validation data.
Comment summary #2: The commenter requested tightening the limit for any
individual unspecified degradation product.
Response: Comment not incorporated. The proposed acceptance criteria are
consistent with the sponsor’s FDA approved limit.
47